THIS WEEK IN

N EWS
F OCUS
eases, says Hahn. “They will open up a lot of
new applications,” Lo agrees.
One major caveat is that the studies so far
have only been able to detect mutations
passed on by the father. Because there’s not
yet a way to completely separate fetal DNA
from the maternal DNA in a woman’s blood,
it’s not possible to tell if a mutation possessed
by the mother has been inherited by the fetus
or if researchers are just seeing the mother’s
DNA. One possible solution may be an epigenetic
marker, such as methylated groups
attached to a gene, that distinguishes fetal
DNA from a mother’s. Lo’s group showed in
2002 that they could make such a
distinction. Another potential
strategy is to use messenger
RNA molecules produced
only by the fetus and not the
mother. Several groups have
recently shown, for example,
that RNA produced by placental
genes can be detected in maternal
blood.
Seeing double
Diagnosing Down syndrome
noninvasively through fetal DNA is
the big prize luring researchers. The potential
demand for such a test is huge, says
Boston University’s Charles Cantor, chief
scientific officer of Sequenom Inc.,
because the rate of Down syndrome is at
least 1 in 270 for mothers over 35. Doctors
can screen for the disorder in the first
trimester by using ultrasound to measure
the dimensions of the fetus’s neck and
checking the levels of several protein markers
in maternal blood; this combination
picks up 85% of cases, albeit with a false
positive rate of 2% to 6%. The International
Down Syndrome Screening group last year
called for this noninvasive strategy to be
offered to all women, but a firm diagnosis
still requires subsequent amniocentesis or
CVS. The $1000 or more cost of these two
tests limits routine use to women over 35,
which means most Down syndrome births
now occur in younger women.
Yet while Down syndrome is easy to
detect if fetal cells are in hand, it’s harder
using cell-free DNA. The reason is that this
condition is caused by an extra chromosome,
rather than a mutation that can be detected
with PCR. So far, for Down syndrome, fetal
DNA can be used to only slightly improve
screening: Overall fetal DNA levels are
higher in women carrying fetuses with Down
syndrome and some other aneuploidies.
Adding a fetal DNA quantity test to other
serum markers for Down syndrome would
boost the detection rate from 81% to
85%, Bianchi’s group has shown.
Still, the real prize is a straightforward,
noninvasive fetal DNA diagnostic for Down
SRY (copies/ml)
60
40
20
0
0 10 20 30 40
60
40
60
40
CASE 1
CASE 2
20
0
0 10 20 30 40
CASE 3
20
0
0 10 20 30 40
Gestation (week)
Baby signs. Cell-free fetal DNA levels rise during
pregnancy, as shown in three future moms.
syndrome that’s as accurate as amniocentesis
and CVS. One possible solution is to discover
an epigenetic marker for Down syndrome
that would allow Down-specific
DNA sequences to be amplified with PCR.
Another is to look for fetal mRNA from a
gene expressed by chromosome 21 but not
by the mother’s cells. Cantor estimates that
two dozen groups are working on the problem
and predicts it will be solved in 3 years.
Ethical minefield
Indeed, while research on noninvasive fetal
testing is very competitive—Lo and other
investigators have certainly applied for
many patents—cooperation is common.
Cross-lab studies like the one sponsored by
NICHD have nurtured the field, and they are
continuing thanks to a new 5-year, €12 million
European Union project called Special
Advances in Fetal Evaluation (SAFE) that
involves 52 institutional partners. “I think
this is a positive example of a new technology
being rigorously investigated before it
filters into practice,” says gynecologist
Wolfgang Holzgreve of the Basel group.
The need for caution makes some scientists
uncomfortable with Baby Gender
Mentor. The company offering the test,
Acu-Gen Biolabs in Lowell, Massachusetts,
claims it works at 5 weeks of gestation at
99.9% accuracy. But Bianchi questions that
figure, noting that a cross-lab study of gender
detection published last year found that
sensitivity varied widely among labs. A
company spokesperson says the 99.9% figure
is based on 20,000 births but notes that
the company won’t publish results until it
has patented its technology.
There’s little chance for outside experts
to scrutinize that accuracy claim. Food and
Drug Administration approval is not needed
as long as the blood sample goes to a lab and
the test is sold as a service rather than as a
kit. Like other genetic tests, “[this] is opening
up gaps in the oversight system,” says
Kathy Hudson, director of the Genetics and
Public Policy Center at Johns Hopkins University
in Baltimore, Maryland. It’s not just
the U.S. that does not regulate such testing.
A Canadian company called Paragon
Genetics has been offering a fetal DNA
gender test for more than 2 years. The firm’s
quiet marketing of it hasn’t drawn as much
criticism as Baby Gender Mentor, in part
because it follows the practice of many fetal
DNA researchers by using fresh maternal
blood, instead of dried blood spots. It also
suggests that samples be taken 10 weeks
into pregnancy.
As for concerns that some couples
could use fetal DNA gender tests to end a
pregnancy, Paragon Genetics lab director
Yuri Melekhovets argues that parents can
already do that based on ultrasound tests
early in the second trimester. Still, Lo’s
group has gone so far as to stipulate in
licensing agreements with companies that
its technology can’t be used for sex selection.
The SAFE project, meanwhile, is
funding a study of the implications of
using early fetal DNA testing, especially if
costs fall enough to make it feasible for
couples in countries such as India and
China where female children may be
viewed as less desirable. “Especially in
‘one child’ countries, there is a risk that
this [test] can be abused,” says Hulten, the
SAFE project’s coordinator.
Another troubling ethical issue for some
is how abortion rates could be affected by
the advent of widespread, accurate fetal
DNA testing for many genetic diseases.
Although abortions may increase, Bianchi
points out that mothers who keep a child
with a disease could also benefit from the
prenatal diagnosis. A survey by her group
found that mothers who went to term after
learning that they were carrying a fetus
with Down syndrome were better able to
cope psychologically once the child was
born than mothers who learned of their
baby’s disorder at birth. Based on that finding,
if fetal DNA testing fully comes of age,
it may provide many potential parents with
news that’s difficult to hear, but it could
also give them time to decide what’s right
for them and accept their decision.
–JOCELYN KAISER
SOURCE: D. LO, AM. HUM. GENET. 62, 768-775 (1998); ILLUSTRATION: JUPITER IMAGES
1478
2 SEPTEMBER 2005 VOL 309 SCIENCE www.sciencemag.org